Papillomaviruses are found in higher vertebrates and have been associated with benign proliferative lesions. A subgroup of viruses are associated with lesions which can progress to malignancy. There are currently over 65 different human papillomaviruses and six different bovine papillomaviruses. The life cycle of these viruses is closely linked to the differentiation program of squamous epithelial cells which are the natural host cell for these viruses. The bovine papillomavirus type 1 (BPV-1) has served as the prototype of the papillomaviruses for genetic and molecular studies. BPV-1 virus readily transforms a variety of rodent cells in tissue culture, and a unique feature of the transformed cells is that the viral DNA often remains as the stable extrachromosomal plasmid within the cells. The laboratory's studies have been designed to focus on the normal virus host cell interactions of BPV-1 in order to gain insight into the viral and cellular factors which regulate viral gene expression and carcinogenic progression. These studies have demonstrated that both the viral E1 and E2 proteins play important roles in both transcriptional regulation and replication. More recent studies have focused on the identification of viral cis and transregulatory elements which are involved in the maintenance of latency. The viral E1 and E2 proteins have been shown to repress expression of the E6, E7, and E5 oncogenes through multiple mechanisms.